Muscle Hypermetabolism and Pruritus in Amphiphysin‐IgG‐Positive Stiff‐Person Syndrome

An 84-year-old woman presented with 3 months of progressive pruritus, stiffness, and painful spasms in the neck, shoulders, and arms. Symptoms initially localized to the cervical region before spreading to the right arm after 1 month and the left arm 3 weeks later (Video 1). She also had gait instability, mild confusion, and unintentional weight loss. Contrast-enhanced magnetic resonance imaging of the brain, cervical, and thoracic spine was unrevealing. 18F-fluorodeoxyglucose positron emission tomography computed tomography (18F-FDG PET/CT) revealed hypermetabolism in a left breast mass, regional lymph nodes, and involved stiff musculature (Fig 1C). Cerebrospinal fluid showed mild pleocytosis (6 white blood cells/mm3) and >5 oligoclonal bands. She received intravenous methylprednisolone 1 g/day and intravenous immunoglobulin (IVIG) 0.4 g/kg/day for 5 days, and diazepam up-titrated to 4 mg 3 times a day, resulting in resolution of spasms and pruritus, and clinical improvement of stiffness and mobility. Neural autoantibody testing was positive for anti-amphiphysin (Fig 1A, B) compatible with paraneoplastic stiff-person syndrome (SPS). She underwent left mastectomy with axillary lymph node dissection. Histopathology showed invasive ductal carcinoma with neuroendocrine features (Fig 1D). She started adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy given intravenously every 21 days for 8 cycles. At the 3-month follow-up after the initiation of treatment, she was substantially less stiff without pruritus or spasms. SPS is characterized by muscle rigidity and spasms and associates with autoantibodies against inhibitory synaptic proteins, such as glutamic acid decarboxylase (GAD), glycine receptor, or amphiphysin.1 Amphiphysin-IgG-positive SPS is distinct as it is frequently paraneoplastic, often linked to underlying malignancies, most commonly breast cancer.2, 3 Paraneoplastic SPS primarily involves stiffness and spasms in the neck and proximal arm muscles, which may correspond to metabolic hyperactivity in affected muscles on FDG-PET, as seen in our patient, like previously reported in SPS with anti-GAD.1, 2 FDG-PET is likely helpful by both detecting metabolic hyperactivity in affected muscles and identifying malignancies associated with the disorder.1 The paraneoplastic form is also uniquely associated with pruritus as an early symptom.2, 3 In our case, the tumor demonstrated markers of neuroendocrine differentiation (ie, chromogranin and synaptophysin), and the pruritus is postulated to represent either a paraneoplastic immune-mediated phenomenon given the improvement after initiation of immunotherapy, or a direct effect of the breast carcinoma, as tumors with neuroendocrine features may secrete substances that contribute to pruritus.2, 4 Hence, underlying malignancy, particularly breast carcinoma, must be excluded in adult female patients presenting with neck and upper limb stiffness and spasms, especially when accompanied by unexplained pruritus.2-4 Early recognition of these clinical and imaging findings can prompt timely investigation for underlying malignancies and treatment which may improve neurological outcomes and overall prognosis.2, 3 Our patient symptomatically improved and stabilized with intravenous methylprednisolone, IVIG, and benzodiazepines, followed by surgical resection of the breast carcinoma and adjuvant chemotherapy. This therapeutic approach aligns with current expert opinion to use combined immunotherapy, anti-spasticity drugs, and cancer-directed treatment.2, 3 Further studies are warranted to elucidate whether muscle metabolic changes seen by FDG-PET and pruritus can assist in early diagnosis and monitoring of treatment response in paraneoplastic SPS. The authors thank Dr John Mills, PhD at Mayo Clinic Laboratories for providing anti-amphiphysin-positive tissue immunofluorescence and immunoblot images, and Dr Stephen Scharf, MD, for the FDG-PET/CT images. S.A. and S.N. contributed to conception and design of the study. S.A., J.Y., S.H., and S.N. contributed to the acquisition and analysis of data. S.A., J.Y., S.H., and S.N. contributed to drafting the text or preparing the figures. The authors declare that there are no conflicts of interest relevant to this work. De-identified data is available to any qualified investigators upon reasonable request. Video 1 A woman displaying neck and arm stiffness and muscle rigidity due to anti-amphiphysin stiff-person syndrome and breast cancer pretreatment. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.